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The increasing volumes of data produced at light sources such as the Linac Coherent Light Source (LCLS) enable the direct observation of materials and molecular assemblies at the length and timescales of molecular and atomic motion. This exponential increase in the scale and speed of data production is prohibitive to traditional analysis workflows that rely on scientists tuning parameters during live experiments to adapt data collection and analysis. User facilities will increasingly rely on the automated delivery of actionable information in real time for rapid experiment adaptation which presents a considerable challenge for data acquisition, data processing, data management, and workflow orchestration. In addition, the desire from researchers to accelerate science requires rapid analysis, dynamic integration of experiment and theory, the ability to visualize results in near real-time, and the introduction of ML and AI techniques. We present the LCLS-II Data System architecture which is designed to address these challenges via an adaptable data reduction pipeline (DRP) to reduce data volume on-thefly, online monitoring analysis software for real-time data visualization and experiment feedback, and the ability to scale to computing needs by utilizing local and remote compute resources, such as the ASCR Leadership Class Facilities, to enable quasi-real-time data analysis in minutes. We discuss the overall challenges facing LCLS, our ongoing work to develop a system responsive to these challenges, and our vision for future developments.

Background: There is no definitive objective measure for diagnosis of thoracic outlet syndrome (TOS), and functional capacity testing on standardized rehabilitation exercises before and after an anterior scalene muscle block (ASMB) has the potential to serve as a predictor of response to surgery and to improve diagnostic accuracy in these cases., Methods: Patients evaluated for TOS underwent ASMB as a diagnostic test and were retrospectively reviewed. Functional capacity scores were recorded for patients performing repetitive motion exercises immediately before ASMB, 15 minutes after ASMB, and at a minimum of 6 weeks after thoracic outlet decompression (TOD). The primary outcome of interest was correlation between the pre- to post-ASMB difference and the pre-ASMB to postoperative difference with respect to 3 functional work capacity scores., Results: The average change in time-to-fatigue and work product between pre- and post-ASMB of all exercises was an increase of 39.5% and 53.8%, respectively. The greatest pre-ASMB to post-TOD difference was seen for the Extremity Abduction Stress Test with an average improvement of 109.7% and 150.4% for time-to-fatigue and work product, respectively. The degree of percent improvement post-ASMB correlated positively with the degree of percent improvement post-TOD for all exercises with respect to work product and time-to-fatigue., Conclusions: Patient response to ASMB as measured by functional capacity on rehabilitation exercises predicted objective functional outcomes following TOD. Post-ASMB outcomes correlated with post-TOD outcomes. The ASMB can be used to assist in diagnosing TOS and provide a surrogate for expectation in patients considering undergoing neurogenic TOD., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Forage fishes are key energy conduits that transfer primary and secondary productivity to higher trophic levels. As novel environmental conditions caused by climate change alter ecosystems and predator-prey dynamics, there is a critical need to understand how forage fish control bottom-up forcing of food web dynamics. In the northeast Pacific, northern anchovy ( Engraulis mordax ) is an important forage species with high interannual variability in population size that subsequently impacts the foraging and reproductive ecology of marine predators. Anchovy habitat suitability from a species distribution model (SDM) was assessed as an indicator of the diet, distribution and reproduction of four predator species. Across 22 years (1998-2019), this anchovy ecosystem indicator (AEI) was significantly positively correlated with diet composition of all species and the distribution of common murres ( Uria aalge ), Brandt's cormorants ( Phalacrocorax penicillatus ) and California sea lions ( Zalophus californianus ), but not rhinoceros auklets ( Cerorhinca monocerata ). The capacity for the AEI to explain variability in predator reproduction varied by species but was strongest with cormorants and sea lions. The AEI demonstrates the utility of forage SDMs in creating ecosystem indicators to guide ecosystem-based management.

Climate change and other human activities are causing profound effects on marine ecosystem productivity. We show that the breeding success of seabirds is tracking hemispheric differences in ocean warming and human impacts, with the strongest effects on fish-eating, surface-foraging species in the north. Hemispheric asymmetry suggests the need for ocean management at hemispheric scales. For the north, tactical, climate-based recovery plans for forage fish resources are needed to recover seabird breeding productivity. In the south, lower-magnitude change in seabird productivity presents opportunities for strategic management approaches such as large marine protected areas to sustain food webs and maintain predator productivity. Global monitoring of seabird productivity enables the detection of ecosystem change in remote regions and contributes to our understanding of marine climate impacts on ecosystems., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Perioperative pain management in surgery of the hand and upper extremity relies on a multimodal approach involving systemic, local, and presurgical considerations. A pain management plan should be tailored to each patient. Management of pain of patients undergoing upper extremity surgery begins before surgical intervention and continues postoperatively. Patient education, setting expectations, psychological interventions, and addressing risk factors associated with postoperative pain are critical to successful pain management. Intraoperative anesthesia is accomplished via a variety of means. Cryotherapy, transcutaneous electrical nerve stimulation, acupuncture, massage, and localized heat are used in concert with pharmacologic therapies postoperatively to continue pain management., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This article discusses the pathophysiology, presentation, cause, and treatment of ischemic pain in the surgical patient. Causes of ischemic pain vary but all fundamentally cause local acidosis in the peripheral tissues, which causes signals to be passed through ascending pain pathways to the thalamus and eventual cerebral cortex where it is interpreted as ischemic pain. Ischemic pain is classically associated with an insidious onset but can present in the acute or chronic setting. Treatments are aimed at improving perfusion to the affected tissue. Surgical options include repairing damaged vessels, bypassing diseased vessels, performing thrombectomy, or embolectomy. Numerous conservative therapies exist., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Lysosomal membrane permeabilization (LMP) is observed under many pathological conditions, leading to cellular dysfunction and death. However, the mechanisms by which lysosomal membranes become leaky in vivo are not clear. Our data demonstrate that LMP occurs in neurons following controlled cortical impact induced (CCI) traumatic brain injury (TBI) in mice, leading to impaired macroautophagy (autophagy) and neuronal cell death. Comparison of LC-MS/MS lysosomal membrane lipid profiles from TBI and sham animals suggested a role for PLA2G4A/cPLA2 (phospholipase A2, group IVA [cytosolic, calcium-dependent]) in TBI-induced LMP. Activation of PLA2G4A caused LMP and inhibition of autophagy flux in cell lines and primary neurons. In vivo pharmacological inhibition of PLA2G4A attenuated TBI-induced LMP, as well as subsequent impairment of autophagy and neuronal loss, and was associated with improved neurological outcomes. Inhibition of PLA2G4A in vitro limited amyloid-β-induced LMP and inhibition of autophagy. Together, our data indicate that PLA2G4A -mediated lysosomal membrane damage is involved in neuronal cell death following CCI-induced TBI and potentially in other neurodegenerative disorders. Abbreviations : AACOCF 3 , arachidonyl trifluoromethyl ketone; ACTB/β-actin, actin, beta; AD, Alzheimer disease; ATG5, autophagy related 5; ATG7, autophagy related 7; ATG12, autophagy related 12; BECN1, beclin 1, autophagy related; C1P, ceramide-1-phosphate; CCI, controlled cortical impact; CTSD, cathepsin D; CTSL, cathepsin L; GFP, green fluorescent protein; IF, immunofluorescence; LAMP1, lysosomal-associated membrane protein 1; LAMP2, lysosomal-associated membrane protein 2; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LMP, Lysosomal membrane permeabilization; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; MAP1LC3/LC3, microtuble-associated protein 1 light chain 3; NAGLU, alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); PC, diacyl glycerophosphatidylcholine; PE, diacyl glycerophosphatidylethanolamine; PE-O, plasmanyl glycerophosphatidylethanolamine; PE-P, plasmenyl glycerophosphatidylethanolamine; PLA2G4A/cPLA2, phospholipase A2, group IVA (cytosolic, calcium-dependent); RBFOX3, RNA binding protein, fox-1 homolog (C. elegans) 3; RFP, red fluorescent protein; ROS, reactive oxygen species; SQSTM1, sequestosome 1; TUBA1/α-tubulin, tubulin, alpha; TBI, traumatic brain injury; TFEB, transcription factor EB; ULK1, unc-51 like kinase 1.

Recent studies indicate a causative relationship between defects in autophagy and dopaminergic neuron degeneration in Parkinson disease (PD). However, it is not fully understood how autophagy is regulated in the context of PD. Here we identify USP24 (ubiquitin specific peptidase 24), a gene located in the PARK10 (Parkinson disease 10 [susceptibility]) locus associated with late onset PD, as a novel negative regulator of autophagy. Our data indicate that USP24 regulates autophagy by affecting ubiquitination and stability of the ULK1 protein. Knockdown of USP24 in cell lines and in human induced-pluripotent stem cells (iPSC) differentiated into dopaminergic neurons resulted in elevated ULK1 protein levels and increased autophagy flux in a manner independent of MTORC1 but dependent on the class III phosphatidylinositol 3-kinase (PtdIns3K) activity. Surprisingly, USP24 knockdown also improved neurite extension and/or maintenance in aged iPSC-derived dopaminergic neurons. Furthermore, we observed elevated levels of USP24 in the substantia nigra of a subpopulation of idiopathic PD patients, suggesting that USP24 may negatively regulate autophagy in PD. Abbreviations : Bafilomycin/BafA: bafilomycin A 1 ; DUB: deubiquitinating enzyme; iPSC: induced pluripotent stem cells; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; nt: non-targeting; PD: Parkinson disease; p-ATG13: phospho-ATG13; PtdIns3P: phosphatidylinositol 3-phosphate; RPS6: ribosomal protein S6; SNPs: single nucleotide polymorphisms; TH: tyrosine hydroxylase; USP24: ubiquitin specific peptidase 24.

Bi-allelic GBA1 mutations cause Gaucher's disease (GD), the most common lysosomal storage disorder. Neuronopathic manifestations in GD include neurodegeneration, which can be severe and rapidly progressive. GBA1 mutations are also the most frequent genetic risk factors for Parkinson's disease. Dysfunction of the autophagy-lysosomal pathway represents a key pathogenic event in GBA1 -associated neurodegeneration. Using an induced pluripotent stem cell (iPSC) model of GD, we previously demonstrated that lysosomal alterations in GD neurons are linked to dysfunction of the transcription factor EB (TFEB). TFEB controls the coordinated expression of autophagy and lysosomal genes and is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1). To further investigate the mechanism of autophagy-lysosomal pathway dysfunction in neuronopathic GD, we examined mTORC1 kinase activity in GD iPSC neuronal progenitors and differentiated neurons. We found that mTORC1 is hyperactive in GD cells as evidenced by increased phosphorylation of its downstream protein substrates. We also found that pharmacological inhibition of glucosylceramide synthase enzyme reversed mTORC1 hyperactivation, suggesting that increased mTORC1 activity is mediated by the abnormal accumulation of glycosphingolipids in the mutant cells. Treatment with the mTOR inhibitor Torin1 upregulated lysosomal biogenesis and enhanced autophagic clearance in GD neurons, confirming that lysosomal dysfunction is mediated by mTOR hyperactivation. Further analysis demonstrated that increased TFEB phosphorylation by mTORC1 results in decreased TFEB stability in GD cells. Our study uncovers a new mechanism contributing to autophagy-lysosomal pathway dysfunction in GD, and identifies the mTOR complex as a potential therapeutic target for treatment of GBA1 -associated neurodegeneration., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Background: Histological analysis remains a cornerstone approach for the investigation of peripheral nerve regeneration. This study investigates a newly recognized histological difference between peripheral and central zones within the regenerating nerve trunks., Purpose: The purpose of the study was to determine if the nerve axonal area (NXA) in regenerating peripheral nerves differs within central and peripheral areas, when viewed in cross-section., Methods: A total of 14 rats were divided into two groups, and subjected to different injuries to the right sciatic nerve. Group 1: Transection injury with immediate repair. Group 2: Crush injury without any treatment. The left sciatic nerve was left uninjured and served as a control in each rat. Following 4 weeks of recovery, nerve trunk cross-sections were prepared. Computerized techniques were then employed to divide nerve sections into central and peripheral zones and calculate corresponding NXA values for subsequent statistical analysis., Results: NXA of injured nerves was greater within peripheral as compared with the central zones, independent of injury type (p < 0.05). No statistically significant difference existed within the control groups or between the injury methods with regards to NXA regeneration extent., Conclusion: NXA in regenerating peripheral nerves was greater in the peripheral zones than within the central zones., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

This study examined population density, habitat and diet of Dasyatis marianae, a recently discovered species, in the reef complex of Maracajaú in Rio Grande do Norte state, Brazil. The highest concentration of D. marianae occurred in seagrass beds. Habitat use differed significantly between sex and age classes, with females and juveniles using areas other than reefs. Females utilized primarily seagrass beds and juveniles occurred mainly along the sandy bottom near the beach, highlighting the importance of protecting these areas. Dasyatis marianae diet was characterized primarily by crustaceans (91·9% index of relative importance, I RI ), including shrimp, crabs and lobsters. The availability of prey in different habitat types influences occupation by D. marianae, but the prey selectivity of D. marianae, among other factors, may affect this relationship. Intense shrimp and lobster fishing in the region probably has an effect on preferred prey resources of this ray. Information on feeding habits of this species contributes to a better understanding of trophic dynamics and food webs, which is critical if ecosystem principles are to be integrated into fisheries management., (© 2015 The Fisheries Society of the British Isles.)

Buprenorphine has been approved for heroin detoxification, but little is known about its impact on everyday practice. Concerns about buprenorphine include expense, limited knowledge about its use, patient limits, and social and clinical attitudes regarding opioid treatment for heroin dependence. On the other hand, randomized clinical trials suggest that buprenorphine is superior to clonidine with regard to withdrawal symptom relief. In June 2004, a community-based residential medical detoxification center switched from clonidine to buprenorphine treatment for all new and returning heroin clients. This study is a retrospective chart review of subject outcomes with clonidine (n = 100) versus buprenorphine (n = 100). Bivariate analysis suggested few cohort differences in pretreatment demographics and client characteristics. In contrast, buprenorphine was significantly associated with increased length of stay and treatment completion. The positive associations between buprenorphine and both treatment completion and length of stay persisted and were slightly enhanced after regression analysis adjusted for potential confounders. Additionally, clinical staff reported better subject engagement in treatment and psychosocial group sessions. This single-site study is an example of successful integration of an evidence-based treatment into community-based practice.